Alcy Torres

Attention-deficit/hyperactivity disorder in pediatric patients with epilepsy: review of pharmacological treatment.

Attention-deficit/hyperactivity disorder (ADHD) in children with epilepsy is a common source of impairment. Based on review of Medline indexed articles, meeting abstracts, and data requested from drug manufacturers, a summary of evidence that might guide treatment and research is presented. Methylphenidate (MPH) has shown high response rates and no increase in seizures in small trials. However, low baseline seizure rates, small numbers of subjects, and short observation periods limit the power of these studies to detect increases in seizure risk. Although longer-term effects of MPH and its effects in children with frequent seizures need to be studied, the evidence available at this time best supports use of MPH for the treatment of ADHD not amenable to changes in antiepileptic drugs or improvements in seizure control. This treatment should be part of a biopsychosocial approach. Other agents show promise. Preclinical, retrospective and open-label studies on amphetamines and atomoxetine support undertaking randomized controlled studies of these agents in patients with ADHD plus epilepsy. In contrast, additional data on guanfacine and modafinil should be gathered before undertaking randomized controlled studies with these agents.

Copy number variation plays an important role in clinical epilepsy

To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.

Adaptive phase I study of OROS methylphenidate treatment of attention deficit hyperactivity disorder with epilepsy

OBJECTIVEnThe goal of this study was to pilot a randomized controlled trial of OROS methylphenidate (OROS-MPH) to treat attention deficit hyperactivity disorder (ADHD) plus epilepsy.nnnMETHODSnThirty-three patients, 6-18years of age, taking antiepileptic drugs and with a last seizure 1-60months prior were assigned to a maximum daily dose of 18, 36, or 54mg of OROS-MPH in a double-blind placebo-controlled crossover trial.nnnRESULTSnThere were no serious adverse events and no carryover effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than did placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns require further study.nnnCONCLUSIONnA larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties.

An expert opinion on methylphenidate treatment for attention deficit hyperactivity disorder in pediatric patients with epilepsy.

Methylphenidate (MPH) is one of the most commonly prescribed medications to treat attention deficit hyperactivity disorder (ADHD). Despite the elevated rates of ADHD in children with epilepsy, few studies have examined the use of MPH in this population. Case reports have warned about new-onset seizures in patients treated with MPH, and drug–drug interactions between MPH and antiepileptic drugs (AEDs), as well as antidepressants. However, retrospective chart reviews, open-label trials and controlled trials of MPH in patients with epilepsy and ADHD have noted significant improvements in ADHD symptoms without an exacerbation of seizures or an adverse effect on AED serum levels. This paper reviews the chemistry and mechanisms of action of MPH, as well as preclinical, premarketing clinical trials and postmarketing data relevant to its use in patients with ADHD and epilepsy.

Diagnostic value of electromyography and muscle biopsy in arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC), a clinical syndrome characterized by multiple congenital joint contractures, frequently is caused by lesions in the peripheral nervous system. Two standard tests for the evaluation of the motor unit are nerve conduction studies/electromyography (NCS/EMG) and muscle biopsy. We reviewed the diagnostic value of these two studies in the evaluation of AMC over a 23‐year period, analyzing 38 patients with AMC who had NCS/EMG, muscle biopsy, or both. Final diagnoses were classified as neurogenic (8 patients), myopathic (10 patients), “other” (12 patients), or unknown (8 patients). Neither test alone had consistently high sensitivities, positive predictive values, or specificities. However, when NCS/EMG and muscle biopsy were concordant for neurogenic or myopathic findings, they were more accurate than either test alone, especially for neurogenic diseases. Test results were most commonly discordant in patients with “other” or unknown diagnoses. These findings suggest that when the clinical evaluation indicates a specific syndromic, developmental, or exogenous cause, NCS/EMG and muscle biopsy are not helpful and may not need to be performed. When the history, examination, and genetic evaluation are unrevealing, NCS/EMG and muscle biopsy together provide valuable diagnostic information.

Highly Penetrant Alterations of a Critical Region Including BDNF in Human Psychopathology and Obesity

CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology. DESIGN Case-control study. SETTING Microarray-based comparative genomic hybridization data from 7 molecular diagnostic centers including 38xa0550 affected subjects and 28xa0705 unaffected subjects. PATIENTS Subjects referred to diagnostic screening centers for microarray-based comparative genomic hybridization for physical or cognitive impairment. MAIN OUTCOME MEASURES Genomic copy number gains and losses. RESULTS We report 5 individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities. CONCLUSION Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders.

Tolerability of atomoxetine for treatment of pediatric attention-deficit/hyperactivity disorder in the context of epilepsy

To examine atomoxetines tolerability in patients with epilepsy, we reviewed medical records of all patients with epilepsy who were treated with atomoxetine in a tertiary care pediatric psychopharmacology practice. Twenty-seven patients (10.1 ± 4.2 years, 63% male) with an average seizure frequency at baseline of 7 ± 24 per month (median: 0, range: 0-90) were found. Symptoms of attention-deficit/hyperactivity disorder in twenty-five patients (92.5%) had previously not responded to stimulants. Atomoxetine, average dose 35.2 ± 24.4 mg, was given for a median of 26 weeks (range: 4-141). Seventeen patients (63%) discontinued atomoxetine due to: inadequate response (n=7, 26%), worsening behavior such as increased irritability/activation (n = 7, 26%), nonadherence (n=1, 4%), emerging psychotic-like symptoms (n=1, 4%), and appetite decrease and tremor (n=1, 4%). There were no discontinuations because of seizure exacerbation. Atomoxetine dose, epilepsy etiology, seizure type, and comorbid psychiatric disorders did not predict discontinuation. No safety problems of sufficient magnitude to preclude prospective studies of atomoxetine in children with epilepsy were found.

Age of first exposure to American football and long-term neuropsychiatric and cognitive outcomes

Previous research suggests that age of first exposure (AFE) to football before age 12 may have long-term clinical implications; however, this relationship has only been examined in small samples of former professional football players. We examined the association between AFE to football and behavior, mood and cognition in a large cohort of former amateur and professional football players. The sample included 214 former football players without other contact sport history. Participants completed the Brief Test of Adult Cognition by Telephone (BTACT), and self-reported measures of executive function and behavioral regulation (Behavior Rating Inventory of Executive Function-Adult Version Metacognition Index (MI), Behavioral Regulation Index (BRI)), depression (Center for Epidemiologic Studies Depression Scale (CES-D)) and apathy (Apathy Evaluation Scale (AES)). Outcomes were continuous and dichotomized as clinically impaired. AFE was dichotomized into <12 and ⩾12, and examined continuously. Multivariate mixed-effect regressions controlling for age, education and duration of play showed AFE to football before age 12 corresponded with >2 × increased odds for clinically impaired scores on all measures but BTACT: (odds ratio (OR), 95% confidence interval (CI): BRI, 2.16,1.19–3.91; MI, 2.10,1.17–3.76; CES-D, 3.08,1.65–5.76; AES, 2.39,1.32–4.32). Younger AFE predicted increased odds for clinical impairment on the AES (OR, 95% CI: 0.86, 0.76–0.97) and CES-D (OR, 95% CI: 0.85, 0.74–0.97). There was no interaction between AFE and highest level of play. Younger AFE to football, before age 12 in particular, was associated with increased odds for impairment in self-reported neuropsychiatric and executive function in 214 former American football players. Longitudinal studies will inform youth football policy and safety decisions.

CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46xa0nmol/L may be sufficient to eradicate CNS disease.

Evidence-based decision support for neurological diagnosis reduces errors and unnecessary workup.

Using vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing.